Studies directed towards the stereoselective total synthesis of ilexlactone via a tandem ring-closing enyne metathesis protocol

Article abstract of DOI:10.1016/j.tetlet.2007.10.021

Studies directed towards the stereoselective total synthesis of ilexlactone resulted in the synthesis of bicyclic systems 1a, 1b and ent-1a through tandem ring-closing enyne metathesis using Grubbs' catalyst. The structures of synthetic 1a, 1b and ent-1a

Full text of DOI:10.1016/j.tetlet.2007.10.021

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8721–8724
Studies directed towards the stereoselective total synthesis of
ilexlactone via a tandem ring-closing enyne metathesis protocol
*
Palakodety Radha Krishna and M. Narsingam
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Received 6 July 2007; revised 26 September 2007; accepted 3 October 2007
Available online 6 October 2007
Abstract—Studies directed towards the stereoselective total synthesis of ilexlactone resulted in the synthesis of bicyclic systems 1a, 1b
and ent-1a through tandem ring-closing enyne metathesis using Grubbs’ catalyst. The structures of synthetic 1a, 1b and ent-1a
revealed that the proposed structure for ilexlactone is incorrect.
Ó 2007 Published by Elsevier Ltd.
The ruthenium carbenes developed by Grubbs in the
early 1990s have aroused considerable attention because
of their functional group tolerance and alkene chemo-
malic acid and 1,3-propane diol, independently, via tan-
dem enyne metathesis as the key step. Considering pre-
vious reports on tandem ring-closing enyne metathesis,
it was clear that the substrates utilized so far were either
electron-rich or sterically less crowded alkenes or
alkynes.
6
1
2
selection in alkene metathesis. Kinoshita and Mori
reported ring-closing enyne metathesis with high
catalytic efficiency using Grubbs’ catalyst. After thor-
ough investigations on enyne metathesis, Grubbs intro-
3
duced tandem enyne metathesis in 1994. In this process,
Retrosynthetic analysis revealed that the target com-
pound 1a could be obtained from 2 by tandem ring-
closing metathesis using Grubbs’ catalyst (A) and
subsequent deprotection of the MOM group. Com-
pound 2, in turn, could be obtained from propargyl
alcohol 3 which could be prepared from L-malic acid.
Retrosynthesis of the other isomer, ent-1a revealed that
the key substrate 8 could be derived from chiral alde-
hyde 9, which in turn could be accessed from 1,3-pro-
pane diol.
various dienynes were subjected to ring-closing enyne
metathesis to produce an array of bicyclic systems as
well as highly complex natural products. Thus, tandem
ring-closing enyne metathesis gained much prominence
4
in synthetic organic chemistry. Recently, we became
interested in the synthesis of natural products as well
as the synthesis of diverse compounds using Grubbs’
catalyst. Consequently, we chose the natural product
5
ilexlactone 1a, isolated from Ilex aquifolium, whose
0
structure was determined as a 3-(3 -hydroxycyclopent-
1
0
7
-enyl)-Z-propenic acid-1,5 -lactone, as a synthetic
The synthesis began with known allylic alcohol 4 which
target.
was subjected to Sharpless epoxidation (Scheme 1)
i
[
(ꢀ)-DIPT/Ti(O Pr) /cumene hydroperoxide/CH Cl /
4
2
2
Though the absolute configurations at C-3 and C-5 of 1a
were not firmly established, their relative configuration
was assigned as syn. It was thought logical to synthesize
all the diastereoisomers of ilexlactone. Thus, the synthe-
sis of 1a was initiated with commercially available L-
ꢀ20 °C] affording an epoxy alcohol, which was chlo-
rinated (CCl /Ph P/reflux) and then subjected to a
4
3
base-induced double elimination (LDA/THF/ꢀ78 to
ꢀ40 °C) to afford propargylic alcohol 3 (85%). Next,
the hydroxyl group was protected as its p-methoxyb-
enzyl ether (PMBBr/NaH/THF/0 °C to rt) to furnish an
alkyne (86%), removal of the cyclohexanone protection
(
CSA/MeOH/2 h), selective silylation (TBDMSCl/imid-
Keywords: Tandem ring-closing enyne metathesis; Sharpless asymmet-
ric epoxidation; 1,3-Syn selective reduction; Ilexlactone.
azole/CH Cl /rt) of the primary alcohol followed by
2
2
*
Corresponding author. Tel.: +91 40 27160123x2651; fax: +91 40
7160387; e-mail: prkgenius@iict.res.in
MOM protection (MOMCl/DIPEA/DMAP/CH Cl /
2 2
0 °C to rt) and then removal of the silyl group
2
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.10.021

8722
P. Radha Krishna, M. Narsingam / Tetrahedron Letters 48 (2007) 8721–8724
OMOM OPMB
O
a
O
OH
b
O
O
HO
5
OH
4
3
O
c
O
O
e
OMOM O
OMOM OPMB
d
MOMO
6
2
7a
f
Mes
N
N
Mes
Ph
Hf
Hd
Hg
O
O
Cl
HO
Ru
Cl
He
PCy3
Hb
Hc
Mes = C6H2-2,4,6-(CH3)3
Ha
1a
A
i
Scheme 1. Reagents and conditions: (a) (i) (ꢀ)-DIPT, Ti(O Pr)
4
, cumene hydroperoxide, CH
2
Cl
2
, ꢀ20 °C, 12 h, 85%; (ii) CCl
4 3 3
, Ph P, NaHCO ,
reflux, 1 h, 90%; (iii) LDA, THF, ꢀ78 to ꢀ40 °C, 3 h, 85%; (b) (i) PMBBr, NaH, THF, 0 °C to rt, 86%; (ii) CSA, MeOH, 2 h, 81%; (iii) TBSCl,
imidazole, CH Cl , rt, 84%; (iv) MOMCl, DIPEA, DMAP, CH Cl , 0 °C to rt, 6 h, 86%; (v) TBAF, THF, 0 °C to rt, 8 h, 90%; (c) (i) (COCl)
DMSO, Et N, CH Cl CH I, t-BuOK, THF, 0 °C, 6 h, then added aldehyde, 72%; (d) (i) DDQ, CH Cl :H O (9:1), 0 °C to rt,
, ꢀ78 °C, 91%; (ii) PPh
h, 88%; (ii) acryloyl chloride, DIPEA, CH Cl , 0 °C to rt, 1 h, 92%; (e) Grubbs’ 2nd generation catalyst (A), 5 mol %, CH Cl , 12 h, 74%; (f) (i)
PPTS, n-BuOH, reflux, 2 h, 83%.
2
2
2
2
2
,
3
2
2
3
3
2
2
2
2
2
2
2
2
(
TBAF/THF/rt) provided the desired primary alcohol 5.
hydroxyl group was protected as its p-methoxybenzyl
ether (PMBBr/NaH/THF/0 °C to rt) to afford an alkyne
(86%) followed by deprotection (TBAF/THF/rt) of
TBDPS to furnish a primary alcohol, which was oxi-
dized to the corresponding aldehyde 9 under Swern
conditions.
Swern oxidation of 5 followed by Wittig olefination
(Ph PCH I/t-BuOK/THF/0 °C/6 h) afforded alkene 6
(72%). Deprotection of the PMB–ether in 6 with DDQ
3
3
in CH Cl –H O gave a propargylic alcohol which upon
acryloylation
2
2
2
(acryloyl
chloride/DIPEA/CH Cl )
2 2
resulted in synthon 2. Gratifyingly, the critical tandem
ring-closing enyne metathesis of 2 (A, 5 mol %/
CH Cl /reflux/12 h) led to bicyclic system 7a (74%).
Reaction of 9 (Scheme 3) with vinylmagnesium bromide
afforded an inseparable diastereomeric mixture of allylic
alcohols 12 (80% combined yield in a 1:1 ratio). Com-
pound 12 was protected as its MOM–ether (MOMCl/
DIPEA/DMAP/CH Cl /0 °C to rt) followed by depro-
2
2
Lactone 7a was identified from its spectral data. The
1
H NMR spectrum of 7a indicated the absence of acetyl-
enic and terminal olefinic protons whilst demonstrating
three characteristic olefinic protons as doublets at d 7.18
2
2
tection of the PMB–ether with DDQ in CH Cl –H O
2 2 2
(
6
J = 9.5 Hz), d 6.04 (J = 9.5 Hz) and a broad singlet at d
.13. Further, the mass spectrum had an M+1 peak at
to afford a propargylic alcohol (86%) which upon acry-
loylation (acryloyl chloride/DIPEA/CH Cl ) gave acry-
2
2
1
97 as supporting evidence. Finally, deprotection of
late ester 8 (90%). Treatment of compound 8 with
Grubbs’ catalyst (A, 5 mol %/CH Cl /reflux/12 h)
the MOM ether (PPTS/n-BuOH/reflux/2 h) afforded
the target molecule 1a (83%).
2
2
furnished chromatographically separable bicyclic sys-
tems ent-7a and 7b (74%, combined yield). Deprotection
of the MOM ether of ent-7a and 7b (PPTS/n-BuOH/
reflux/2 h) was conducted independently to afford ent-1a
and its isomer 1b (81% each). To recycle the anti-isomer
1b to ent-1a, we used an oxidation–reduction protocol.
Accordingly, 1b was oxidized (Dess–Martin period-
The synthesis of ent-1a was initiated with known epoxy
alcohol 10 (Scheme 2), which was subjected to chlorina-
tion (CCl /Ph P/reflux) followed by a base-induced dou-
8
4
3
ble elimination (LDA/THF/ꢀ78 to ꢀ40 °C) to afford
propargylic alcohol 11 (85%). Next, the propargylic
OH
O
OPMB
O
a
b
TPSO
OH
TPSO
H
1
0
11
9
Scheme 2. Reagents and conditions: (a) (i) CCl
THF, 0 °C to rt, 86%; (ii) TBAF, THF, 0 °C to rt, 8 h, 90%; (iii) (COCl)
4
, Ph
3
P, NaHCO
3
, reflux, 1 h, 90%; (ii) LDA, THF, ꢀ78 to ꢀ40 °C, 3 h, 85%; (b) (i) PMBBr, NaH,
2
, DMSO, Et N, CH Cl
3
2
2
, ꢀ78 °C, 92%.

P. Radha Krishna, M. Narsingam / Tetrahedron Letters 48 (2007) 8721–8724
8723
O
O
O
O
OH
OPMB
OMOM O
MOMO
MOMO
a
b
c
9
d
7b
12
8
+
O
O
O
O
O
e
HO
O
ent-7a
d
f
1b
13
O
O
HO
ent-1a
Scheme 3. Reagents and conditions: (a) vinyl bromide, Mg, THF, then added 9, 80%; (b) (i) MOMCl, DIPEA, DMAP, CH
2
Cl
, 0 °C to rt, 1 h, 90%; (c) Grubbs’ 2nd generation catalyst
, 12 h, 74%; (d) PPTS, n-BuOH, reflux, 2 h, 81%; (e) Dess–Martin periodinane, CH Cl , 0 °C to rt, 4 h, 85%; (f) NaBH
2
, 0 °C to rt, 6 h, 84%;
(
(
ii) DDQ, CH
A), 5 mol %, CH
2
Cl
2
:H
Cl
2
2 2
O (9:1), 0 °C to rt, 2 h, 86%; (iii) acryloyl chloride, DIPEA, CH Cl
2
2
2
2
4
,
3
CeCl Æ7 H
2
O, EtOH, rt, 2 h, 87%.
1
Table 1. Comparative H NMR (300 MHz, CDCl
3
) data of ilexlactone and compounds 1a/ent-1a and 1b
5
Position
Ilexlactone (reported )
Compound 1a/ent-1a
Compound 1b
1
1
1
H NMR (multi, J = Hz)
H NMR (multi, J = Hz)
H NMR (multi, J = Hz)
H
H
H
H
H
H
H
a
b
c
d
e
f
6.65 (dd, 10.0, 2.0)
6.37 (dt, 10.0, 1.5)
5.87 (s)
4.93 (ddd, 12.5, 5.0, 2.0)
4.67(m)
7.17 (d, 9.6)
6.02 (d, 9.6)
6.10 (br s)
5.16 (t, 7.55)
4.83–4.79 (m)
3.09–2.97 (m)
2.11–1.88 (m)
7.19 (d, 9.63)
6.02 (d, 9.73)
6.10 (br s)
5.67 (t, 6.79)
5.04–5.01 (m)
2.49–2.42 (m)
2.36–2.27 (m)
2.97 (m)
1.68 (m)
g
inane/CH Cl /0 °C to rt) to its corresponding ketone 13
Acknowledgement
2
2
9
and selectively reduced (NaBH /CeCl Æ7H O/EtOH) to
4
3
2
afford ent-1a as the exclusive product (86% over two
One of the authors (M.N.) thanks the CSIR, New Delhi,
for financial support in the form of a fellowship.
1
0
steps). The spectroscopic data (Table 1) of structures
a and ent-1a were found to be different from those of
1
5
ilexlactone reported in the literature.
References and notes
Thus, it may be concluded that the structure proposed
for ilexlactone is incorrect. Out of the four possible di-
astereoisomers, the three synthesized herein do not cor-
respond to the proposed structure, thus discounting
both the anti-isomers as well. Also, a comparative study
of the spectral data leads to the conclusion that the most
downfield proton for ilexlactone, resonating at d 6.65,
can only be rationalized if the ring system is reversed
and modified into an a,b-unsaturated c-lactone fused
with a cyclohexenol thus indicating the probable struc-
ture of ilexlactone to be as shown in Figure 1. The
1
. (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem.
Soc. 1993, 115, 9856–9857; (b) Grubbs, R. H.; Miller, S. J.;
Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452; (c)
Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem.
1994, 59, 4029–4031; (d) Fu, G. C.; Grubbs, R. H. J. Am.
Chem. Soc. 1993, 115, 3800–3801; (e) Fu, G. C.; Grubbs,
R. H. J. Am. Chem. Soc. 1992, 114, 7324–7325; (f) Fu, G.
C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426–
5
427.
2
3
. Kinoshita, A.; Mori, M. Synlett 1994, 1020–1022.
. Kim, S.-H.; Bowden, N.; Grubbs, R. H. J. Am. Chem.
Soc. 1994, 116, 10801–10802.
1
reported H NMR values are likely to match with this
revised structure as it justifies the absence of a b-proton
in the lactone ring and the presence of two olefinic pro-
tons in the cyclohexenol ring. Synthetic efforts are
underway in our laboratories to make this compound.
4
. (a) Radha Krishna, P.; Narsingam, M.; Kannan, V.
Tetrahedron Lett. 2004, 45, 4773–4775; (b) Radha
Krishna, P.; Narsingam, M. J. Comb. Chem. 2007, 9,
62–69; (c) Radha Krishna, P.; Srinivas Reddy, P. Tetra-
hedron 2007, 63, 3995–3999.
5
6
. Thomas, H.; Budzikiewicz, H. Phytochemistry 1980, 19,
HO
O
1
866–1868.
O
. (a) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.;
Mulder, J. A.; Grebe, T. P. Org. Lett. 2002, 4, 2417–2420;
(b) Choi, T.-L.; Grubbs, R. H. Chem. Commun. 2001,
Figure 1. Probable structure of ilexlactone.

8724
P. Radha Krishna, M. Narsingam / Tetrahedron Letters 48 (2007) 8721–8724
1
3
2
648–2649; (c) Wu, C.-J.; Madhushaw, R. J.; Liu, R.-S. J.
1H), 2.11–1.88 (m, 2H, inclusive of 1 –OH); C NMR
(75 MHz, CDCl ): d 164.0, 137.2, 136.5, 134.9, 121.9, 80.6,
74.0, 42.3; IR (thin film): 3090, 1720 cm ; LCMS; 153
Org. Chem. 2003, 68, 7889–7892; (d) Boyer, F.-D.; Hanna,
I.; Ricard, L. Org. Lett. 2001, 3, 3095–3098.
. Radha Krishna, P.; Narasimha Reddy, P. V. Tetrahedron
Lett. 2006, 47, 7473–7476.
3
ꢀ1
+
7
8
9
(M+H) . Anal. Calcd. for C
found: C, 63.05; H, 5.21. Compound 8: H NMR
(300 MHz, CDCl , TMS): d 6.51–6.40 (m, 1H), 6.22–
8 8 3
H O : C, 63.15; H, 5.30%;
1
. Lepage, O.; Kattnig, E.; F u¨ rstner, A. J. Am. Chem. Soc.
3
2
004, 126, 15970–15971.
6.05 (m, 1H), 5.90–5.83 (m, 1H), 5.76–5.46 (m, 2H), 5.31–
5.21 (m, 2H), 4.69–4.62 (m, 1H), 4.53–4.41 (m, 1H), 4.3–
4.05 (m, 1H), 3.38 (s, 1.5 H), 3.28 (s, 1.5H), 2.46 (d, 0.5H,
J = 2.07 Hz), 2.4 (d, 0.5H, J = 2.07 Hz), 2.19–1.89 (m,
. Audran, G.; Mori, K. Eur. J. Org. Chem. 1998, 57–62. 25
1
0. Spectral data of selected compounds. Compound 2: ½aꢁ
D
1
ꢀ
60.7 (c 0.8, CHCl ); H NMR (200 MHz, CDCl , TMS):
3
3
ꢀ
2H); IR (thin film): 3340, 3093, 1722 cm ; LCMS; 225
+
25
1
d 6.45 (dd, 1H, J = 1.46, 16.84 Hz), 6.12 (dd, 1H,
J = 10.25, 16.85 Hz), 5.84 (dd, 1H, J = 2.19, 10.25 Hz),
(M +H). Compound 7b: Colored syrup; ½aꢁ +47.0 (c
D
1
5
6
.76–5.5 (m, 2H), 5.30–5.19 (m, 2H), 4.65 (d, 1H, J =
.59 Hz), 4.50 (d, 1H, J = 6.59 Hz), 4.3–4.19 (m, 1H), 3.38
3 3
0.04, CHCl ); H NMR (300 MHz, CDCl , TMS): d 7.2
(d, 1H, J = 9.55 Hz), 6.16 (br s, 1H), 6.03 (d, 1H,
J = 9.70 Hz), 5.62 (t, 1H, J = 7.53 Hz), 4.84–4.76 (m,
1H), 4.67–4.59 (m, 2H), 3.33 (s, 3H), 2.59– 2.44 (m, 1H),
1
3
(
s, 3H), 2.45 (d, 1H, J = 2.19 Hz), 2.21–1.87 (m, 2H);
C
3
NMR (75 MHz, CDCl ): d 164.8, 137.0, 131.8, 127.8,
1
3
1
3
7
18.2, 93.6, 74.5, 73.9, 73.0, 61.4, 55.5, 40.2; IR (thin film)
2.34–2.19 (m, 1H); C NMR (75 MHz, CDCl
3
): d 161.6,
ꢀ
1
+
335, 3093, 1725 cm ; LCMS; 225 (M +1). Compound
137.2, 133.0, 132.8, 122.8, 96.2, 82.4, 79.8, 55.2, 38.8; IR
25
1
ꢀ1
+
a: Syrup; ½aꢁ ꢀ50.9 (c 0.5, CHCl
3
); H NMR (200 MHz,
(thin film): 3093, 1722 cm ; LCMS: 197 (M +H). Anal.
Calcd. for C10 : C, 61.22; H, 6.16; found: C, 61.16;
H, 6.10. Compound 1b: Syrup; ½aꢁ ꢀ8.66 (c 0.1, CHCl );
D
CDCl
6
4
3
, TMS): d 7.18 (d, 1H, J = 9.55 Hz), 6.13 (br s, 1H),
12 4
H O
2
D
5
.04 (d, 1H, J = 9.55 Hz), 5.16 (t, 1H, J = 7.53 Hz), 4.74–
3
1
.59 (m, 3H), 3.38 (s, 3H), 3.05–2.92 (m, 1H), 2.14–1.97
H NMR (300 MHz, CDCl , TMS): d 7.19 (d, 1H,
3
13
(
m, 1H); C NMR (75 MHz, CDCl
3
): d 163.6, 137.0,
J = 9.63 Hz), 6.1 (br s, 1H), 6.02 (d, 1H, J = 9.73 Hz),
1
35.2, 134.6, 122.0, 96.3, 80.15, 79.46, 55.6, 40.3; IR (thin
5.67 (t, 1H, J = 6.79 Hz), 5.04–5.01 (m, 1H), 2.49–2.42 (m,
ꢀ1
+
13
film) 3093, 1722 cm ; LCMS; 197 (M +H). Anal. Calcd.
for C10 : C, 61.22; H, 6.16; found: C, 61.13; H, 6.05.
1H), 2.36–2.27 (m, 1H); C NMR (75 MHz, CDCl ): d
3
H
12
O
4
161.4, 137.1, 133.1, 132.7, 122.8, 82.5, 79.9, 38.9; IR (thin
2
D
5
1
ꢀ1
+
Compound 1a: Syrup; ½aꢁ ꢀ80.6 (c 0.05, CHCl
3
);
H
film): 3093, 1720 cm ; LCMS; 153 (M+H) . Anal. Calcd.
for C : C, 63.15; H, 5.30; found: C, 63.08; H,
NMR (300 MHz, CDCl
3
,
TMS):
d
7.17 (d, 1H,
8 8 3
H O
25
J = 9.63 Hz), 6.1 (br s, 1H), 6.02 (d, 1H, J = 9.63 Hz),
.16 (t, 1H, J = 7.55 Hz), 4.83–4.79 (m, 1H), 3.09–2.97 (m,
5.19. Compound ent-1a: ½aꢁ +80.0 (c 0.05, CHCl3);
D
5
syrup.